1. Field Of The Invention
This invention relates to novel anthracene compounds useful in the treatment of allergic, inflammatory, and tumor conditions, and to therapeutic compositions containing such compounds. The invention provides therapeutic compositions effective at low doses with low irritancy. The agents of the invention form a distinct class, lacking the anthrone or anthraquinone nucleus.
2. Description Of The Prior Art
Anthracenone derivatives display potent and selective antitumor activity against inter alia GBM and KB cell lines, telomerase inhibition and antioxidant activity, and their mechanism of action, though yet to be defined, may be novel.
The discovery of the antitumor activity of 1,4-bis[(aminoalkyl)amino]anthracene-9,10-diones such as ametantrone (1) and mitoxantrone (2) (see FIG. 1) (Zee-Cheng, R. K. V. et al., J. Med. Chem, 21, 291-294, (1978); Zee-Cheng, R. K. V. et al., J. Pharm. Sci., 71, 708-709, (1982); Murdock, K. C. et al., J. Med. Chem., 22, 1024-1030 (1979)) has led to numerous physicochemical and pharmacological studies on the tumoricidal mechanisms of these chemotypes. Krapcho, A. P. et al., J. Med. Chem., 34, 2373-2380, (1991); Morier-Teissier, E. et al., J. Med. Chem., 36, 2084-2090, (1993).
1,8-Dihydroxy-9(10H)-anthracenone (anthralin; dithranol) (3) (see FIG. 1) is recognized as a potent antipsoriatic agent, and has been in clinical use, especially in European countries, for more than half a century. Unna published the first part of his fundamental monograph on the structure-activity relationships of 1,8-dihydroxy-9(10H)-anthracenone and related hydroxyanthrones in 1916. Unna P. G. Dermatol. Wochenschr., 62, 175-183 (1916). 1-Hydroxy-9-anthrone (4) has been shown by Krebs and Schaltegger (Krebs, A.; Schaltegger, H. Hautarzt, 20, 204-209, (1969)) to comprise the xe2x80x9cminimal basic structure for antipsoriatic activityxe2x80x9d.
The mechanism of the antitumor activity of the anthracene-9,10-diones such as ametantrone (1) and mitoxantrone (2) is probably multimodal in nature. However, a number of studies have indicated that an intercalative interaction with DNA may be a major cellular event. Denny, W. A. Anti-Cancer Drug Design, 4, 241-263 (1989). Mitoxantrone, an anthracene-9,10-dione, has gained an important position in the clinical management of leukemia and lymphomas as well as in combination therapy of advanced breast and ovarian cancers. Faulds, D. et al., Drugs, 41, 400-449 (1991). Although mitoxantrone is endowed with an improved tolerance prolife when compared with doxorubicin and other anthracyclines, significant toxic side effects, notably those associated with myelosuppression and cardiotoxicity, remain. Benekli, M. et al., Ann. Intern. Med., 126, 409 (1997).
Mitoxantrone (2) also shows a cross-resistance to cell histotypes developing resistance against doxorubicin mediated by overexpression of glycoprotein. P. Bailly, J. D. et al., Leukemia, 11, 1523-1532 (1997). Several studies suggest that intercalation into DNA is a major cellular event and this intercalative interaction may serve as an anchor for the drug at specific base pair sites, which is then followed by the critical cell-killing events. The biochemical basis for the cardiotoxicity exhibited by mitoxantrone is not fully understood. It is generally believed that the in vivo reduction of the quinone moiety is probably more related to the cardiotoxic side effects of mitoxantrone than to its mechanism of cytotoxicity. Krapcho, A. P., et al., J. Med. Chem., 41, 5429-5444 (1998).
Antitumor quinones represent one of the largest classes of clinically approved anticancer agents in the U.S.A., second only to the chloroethyl alkylating agents. Antitumor quinones have been selected from the large number of naturally occurring quinones (Moore, H. W. et al., Drugs Expl. Clin. Res., 12, 475-494, (1986)) and from synthetic quinones (Bruce, J. M. ed., Benzoquinones and Related Compounds, Vol. 3, Part 4, 1-306, (1974)). The planar tricyclic system is known to intercalate into DNA base pairs and interfere in the transcription and replication processes of the cell. Johnson, R. K. et al., Cancer Treat. Rep., 63, 425-439, (1979); Lown, J. W. et al., Biochemisty, 24, 4028-4035, (1985). The DNA binding affinity (quantified as a binding affinity constant) and the dissociation rate constant for the DNA-ligand complex have been evaluated. Drug-DNA binding constants for ametantrone (1), mitoxantrone (2) and related congeners with calf thymus DNA show a large sensitivity to the position and number of the OH substitutions and the nature of the charged side chain. Denny, W. A. Anti-Cancer Drug Design, 4, 241-263 (1989).
Anthraquinone-based compounds currently occupy a prominent position in cancer chemotherapy, with the naturally occurring aminoglycoside anthracycline doxorubicin and the aminoanthraquinone mitoxantrone both being in clinical use. These and other experimental anthraquinone derivatives are believed to act at the duplex DNA level, probably through the stabilization of a ternary complex with DNA topoisomerase II. Zunino, F. et al., Anti-Cancer Drug Des., 5, 307-317 (1990).
There is increasing evidence that intercalation into DNA represents an attractive target for the rational design of new anticancer agents in view of its central role in the control of cellular proliferation. Normal human cells undergo a finite number of cell divisions and ultimately enter a nondividing state called replicative senescence. During successive rounds of cell division, this end-replication problem results in telomere shortening and ultimately senescence. As such, the loss of telomeric repeats after each round of cell division has been likened to a xe2x80x9cbiological clockxe2x80x9d limiting the proliferative life span of normal somatic cells. Harley, C. B. et al., Nature, 345, 458-460 (1990). Consequently, telomerase has been proposed as a potentially highly selective target for the development of a novel class of antiproliferative agents.
Additional references disclose 1,4- and 2,6-disubstituted or regioisomeric amidoanthracene-9,10-dione derivatives as inhibitors of human telomerase include Philip J. Perry et al. J. Med. Chem. 41, 3253-3260 (1998) and Philip J. Perry et al. J. Med. Chem. 41, 4873-4884 (1998). However, in order for a therapeutic treatment to be effective, both the inflammatory and hyperproliferative aspects of the condition must be addressed without an increase in toxicity or the lack of patient tolerance observed with existing therapeutic agents.
Substantial evidence suggests that free radicals and active oxygen species play a key role in both the therapeutic activity and side effects of anthracenone derivatives. The generation of free radicals from quinones occurs by addition of an electron to the quinone to form semi-quinone free radicals which then transfer an electron to molecular oxygen to afford superoxide radical anion. The resulting radical anions ultimately lead to hydroxyl radicals which can damage cardiac tissue. Despite the attempts to rationalize the cardiotoxicity of anthracene-9,10-dione antitumor agents, few compounds have been shown to possess both good antitumor activity and little or no cardiotoxicity. Consequently there appears to be no way to predict which compounds will be cardiotoxic and which compounds will not. One is thus confronted with the major problem of designing molecules with high efficacy and no toxicity. Krapcho, A. P. et al., J. Med. Chem., 41, 5429-5444 (1998).
As noted above, cancer is typically characterized by hyperproliferative component. There is thus a continuing need for effective compounds that address these aspects of cancer disease.
The present invention differs from the prior art in the absence of the anthrone or anthraquinone structures. This modification is not suggested by the prior art which teaches the significance of the quinone structure in the antitumor activity of these agents through free radical generation.
The invention satisfies the need for effective therapeutic agents for treating allergic, inflammatory and tumor conditions that minimizes or eliminates undesirable allergic or inflammatory effects.
The present invention is related to 1,8-dichloro-anthracene compounds and analogues thereof, the structure of which is based on the tricyclic ring of anthraquinones. The compounds according to the invention are esters synthesized by the reaction of an acid chloride with 1,8-dichloro-9(10H)-anthracenone and show enhanced antiproliferative activity. However, during their preparation, the characteristic quinone structure is destroyed. These blocked compounds may be further modified by introducing an arylacyl or alkylacyl substituent. The novel 1,8-dichloro-anthracene compounds and analogues thereof have therapeutic utility with respect to allergic, inflammatory or tumor conditions.
Accordingly, in one embodiment of the invention, there is provided an anthracene compound according to Formula I, as defined below, said compound containing a substituent R, wherein R represents a branched or straight chain alkyl group having from 1 to 6 carbon atoms, or a phenyl or benzyl group that may be substituted with at least one substituent selected from the group consisting of a short chain alkyl, carboxyl, carboxyl ester, hydroxy, halogen, nitro, alkoxy, phenyl, benzyl, substituted benzyl and substituted phenyl groups.
In a preferred embodiment of the invention, R represents a substituted phenyl group having at least one substituent selected from the group consisting of methyl, halogen, methoxy and nitro groups.
In another preferred embodiment, R represents a straight or branched chain alkyl group having 1 to 4 carbon atoms, which may be substituted with a group selected from acyl and phenyl groups. Additionally, there are provided compounds which are functional analogs of the compound of Formula III.
The invention further provides therapeutic compositions comprising a therapeutically effective amount of at least one compound of the invention and a pharmaceutically acceptable carrier. These compositions of the invention have antiproliferative effects and antineoplastic effects.
Further additional representative and preferred aspects of the invention are described below according to the following detailed description of the invention. The above objectives and advantages of the invention are illustrative, and not exhaustive, of those which can be achieved by the invention. The examples presented herein are non-limiting. Thus, these and other objectives and advantages of the invention will be apparent from the description herein, both as embodied herein and as modified in view of any variations which will be apparent to those skilled in the art.